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Antimicrobial Agents: new
approvals, new warnings
Michael J. Tan, MD, FACP, FIDSA
Associate Professor of Internal Medicine
NEOMED
Disclosures
1. Speaker Bureaus
• Merck (Cubist)
• Pfizer
2. Research
• Merck(Cubist)
3. Relationships are not relevant to discussion.
Discussion will remain pertinent to labeled indications
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Which of the following is an indication where a fluoroquinolone can
still be considered appropriate first line therapy?
1. Uncomplicated Urinary Tract Infection
2. Acute exacerbation of chronic bronchitis
3. Acute sinusitis
4. Community acquired pneumonia
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Objectives
• Review new antimicrobials
• Review new warning and indications
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New Agents
• Anthim (obiltoxaximab) for treatment of inhalational anthrax
• HIV
o Descovy (emtricitabine and tenofovir alafenamide(TAF))
o Odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide)
• HCV
o Epclusa (sofosbuvir and velpatasvir)
o Zepatier (elbasvir, grazoprevir), HCV Geno 1 or 4.
• Vaccines
o Vaxchora (Cholera vaccine, live, oral)
• C difficile
o Zinplava (bezlotoxumab), recurrent C difficile infection in pateints receiving
antimicrobial treatment
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New antimicrobial agents are still lacking
• Antibacterial approvals are still low
• New approvals still lack coverage of many resistant GNR
o Pseudomonas aeruginosa
o Acinetobacter baumanii
o Stenotrophomonas maltophila
o KPC/CRE
• Costs of new antimicrobials are quite prohibitive
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Selected agents in pipeline
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Solithromycin (class fluoroketolide), CABP, uncomplicated urogenital gonorrhea
Eravacycline (class tetracycline), cIAI, cUTI,
Carbavance (vaborbactam + meropenem), cUTI, cIAI, pneumonia, resistant GNR
Taksta (fusidic acid), ABSSSI, PJI?
Cadazolid (quinolonyl-oxazolidinone), C difficile
Imipenem/cilastatin + relebactam, cUTI, cIAI, pneumonia, resistant GNR
Lefamulin (pleuromutillin), ABSSSI, pneumonia, PJI, osteo?
Ceftaroline + avibactam, Resistant GNR
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Old drugs, new uses
• Steno, acinetobacter: minocycline
• Acinetobacter: colistin
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Fluoroquinolones
• 7/26/16, FDA approved safety labeling changes to enhance warning about their
association with disabling and potentially permanent side effects and to limit their use
in patient with less serious bacterial infections.
• Both Oral and Injectables are associated with nerve, muscle, tendon AEs
• Risk generally outweighs benefits in:
o Acute bacterial sinusitis
o Acute exacerbation of chronic bronchitis
o Uncomplicated urinary tract infections
• In above listed conditions, FQ should be reserved for use in patients with these
conditions who have no alternative treatment options.
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Fluoroquinolones
• Worry about CDI, QTc prolongation, CNS effects, interactions, tendinopathy
• Before writing for levofloxacin or ciprofloxacin, ask:
o Does the patient require an antimicrobial?
o Are these your best options for
• UTI/Cystitis?
• Sinusitis?
• AECOPD/AECB?
• Pneumonia?
• Intraabdominal infection?
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Ceftolozane/Tazobactam (Zerbaxa®)
• Cubist, approved December 2014
• Cephalosporin + B-lactamase inhibitor
o Extended gram negative, P aeruginosa, ESBL activity
• Indications (due to susceptible bacteria):
o Complicated intraabdominal infection (CIAI) + metronidazole
• E cloacae, E coli, K pneumo, K oxytoca, P mirabilis, P aeruginosa, B
fragilis, S anginosus, S constellatus, S salivarius
o Complicated urinary tract infection
• E coli, K pneumo, P mirabilis, P aeruginosa
• Dosages
o Crt cl > 501.5g (1g/0.5) IV q8h
o Crt cl 30-50750mg (500mg/250mg) IV q8h
o Crt cl 15-29375mg (250mg/125mg) IV q8h
o Crt cl <15750mg (500mg/250mg) IV x1, 150mg (100/50) q8h
Ceftolozane/Tazobactam (Zerbaxa®)
• Unique aspects
o IV Only
o Similar AE profile to other cephalosporins
o Pregnancy Cat B
o *Anaerobic activity, but studies done with metro
o Increased ESBL activity
o No KPC or metallo beta-lactamase activity
o Retains activity against most resistant Pseudmonas
• Geriatrics, renal impairment
o In cIAI vs. meropenem, cure rate lower in 65 and older
• Not seen in cUTI
o In cIAI vs. meropenem, cure rate lower in crt cl 30-50
• Similar trend seen in cUTI vs. levoflox in crt cl 30-50
Ceftazidime/avibactam (Avycaz®)
• Actavis (now Allergan), approved February 2015
• Cephalosporin (3rd gen) with new B-lactamase inhibitor
o Avibactam
• Inhibits AmpC, KPC, but NOT ESBL or NDM-1
• Indications (due to susceptible bacteria), 18 and older
o Complicated intra-abdominal infection, in combination with metronidazole (E coli, K
pneumo, P mirabilis, Providencia stuartii, E cloacae, K oxytoca, P aeruginosa)
o Complicated urinary tract infection, including pyelonephritis (E coli, K pneumo,
Citrobacter koseri, Citrobacter, freundii, Proteus spp, E cloacae, E aerogenes, P
aeruginosa
• Dosages
o 2.5g (2g/0.5g) over 2h q8h
Ceftazidime/avibactam (Avycaz®)
• Dosages
o >50mL/min2.5g (2g/0.5g) over 2h q8h
o 31-501.25g (1g/0.25g) over 2h q8h
o 16-300.94g (0.75g/0.19g) over 2h q12h
o 6-150.94g (0.75g/0.19g) over 2h q24h
• Contraindications
o Hypersensitivity to ceftaz/avi, ceftaz, cephs
• Warnings
o cIAI, cure rates lower in CrtCl 30-50 vs. >50. Dose in this subgroup was 33% less
than what is recommended
ceftazidime
avibactam
Ceftazidime/avibactam (Avycaz®)
• Unique aspects
o IV Only
o Similar AE profile to other cephalosporins
o Pregnancy Cat B
o Minimal anaerobic activity, need metro
o Increased KPC/CRE activity
o No ESBL or metallo beta-lactamase activity
o Anti-Pseudomonal
• EXPENSIVE
• Currently under drug shortage through 1st quarter 2017
Dalbavancin (Dalvance®)
• Indication for acute bacterial skin and skin structure infections caused
susceptible strains of Gram positive microorganisms (including MRSA)
o Non-inf compared with vanc/linezolid
• Lipoglycopeptide
• Effective half life of 8.5d (204 hrs)
• 1000mg IV over 30min x1 followed by 500mg IV over 30min x1 (7d later)
o INDICATION UPDATED for 1 dose
• Renal impairment (<30mL/min not on scheduled HD)
o 750mg IV over 30 min x1 followed by 375mg IV over 30 min x1 (7d later) No
recommendations for HD patients.
o May dialyze with high permeability membranes
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Dalbavancin (Dalvance®)
• Unique aspects
o LONG half-life
o Two doses for ABSSSI, but will two doses get done?
o How do you deal with drug reactions and drug interaction issues?
o Redman can happen with rapid infusion
o Category C
• Currently one indication, potential for abuse?
• Quite expensive
o At least $1500/500mg vial
o May reduce cost by reducing hospitalization
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Oritavancin (Orbactiv®)
• Indication for acute bacterial skin and skin structure infections caused
susceptible strains of Gram positive microorganisms (including MRSA)
o Non-inf compared with vancomycin
• Lipoglycopeptide
• Terminal half life of 245h, clearance 0.445L/h
• 1200mg IV over 3h x1 (reconstitute from 400mg vials)
• Renal impairment >30mL/min, no dose adjustment required. <30mL/min no
recommendation
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Oritavancin (Orbactiv®)
• Unique aspects
o LONG half-life, SINGLE dose for ABSSSI
o How do you deal with drug reactions and drug interaction issues?
o Redman can happen with rapid infusion
o More cases of osteomyelitis reported in oritavancin arm as compared with
vancomycin arm.
o Artificially prolonged aPTT for 48h and PT/INR for up to 24h.
o Category C
• Currently one indication, potential for abuse?
• Expensive, but less than dalbavancin
o May reduce cost by reducing hospitalization
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Bezlotoxumab (Zinplava™)
• Approved 10/21/16
• Monoclonal antibody to C difficile toxin B
o Binds toxin B and neutralizes preventing binding to mucosa
• T1/2 about 19 days.
• Efficacy through 12 weeks
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Merck PI
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Bezlotoxumab (Zinplava™)
• Must be used in combination with anti-CD therapy (Metro/Vanco/Fidaxo)
• Comes as 1000mg/40cc solution in single dose vial
o Dosed at 10mg/kg IV over 60 min x1. (Conc 1mg/mL to 10mg/mL)
• No contraindications
• Warnings:
o Heart failure was reported more commonly in bezlotoxumab treated patient with a
history of CHF.
o AEs: Nausea, pyrexia, headache
• Questions:
o Cost?
o Who should get it?
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